Summary of Work: Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. There have been a number of hypotheses for the diminished immune responses observed in elderly subjects including involution of the thymus, active immunosuppression, replication senescence of immune cells, cellular signaling defects, and alterations in cytokine expression profiles. A series of clinical studies has revealed that elderly subjects, in contrast to their younger counterparts, exhibit poor cellular and humoral immune responses to vaccines even in the presence of standard adjuvants. Currently, many laboratories are focusing their research efforts into developing more effective stimulants for use with known vaccines to be tested with elderly populations. However, the poor description of alterations in innate and acquired immune function during the aging process have limited therapeutic intervention. This projects utilizes peripheral blood obtained from normal healthy volunteers of different ages to gain insight into the biological, biochemical, and molecular mechanisms underlying age-associated changes in human immune function. In comparison with immune cells obtained from younger individuals, aged leukocytes also display distinctive patterns of protein phosphorylation, cytokine synthesis and gene expression, effects on cell migration and trafficking, and cell-cycle progression. More specific efforts are underway to examine differences in the make-up of lipid rafts within the cell membranes of young and aged lymphocytes. While obtaining the required number of white blood cells has hampered our progress on this project, the addition of the new GRC Apheresis Unit is a major step forward in examining age-related changes in many of the aforementioned studies.